A central feature of addiction is compulsive drug taking, characterized by loss of control over drug use despite adverse physiological and social consequences. A prevailing theory in the neurobiology of cocaine addiction is that repeated drug exposure imposes persistent neurochemical and molecular changes, e.g. altered gene expression, in the mesocorticolimbic brain circuitry underlying reward. These cocaine-induced neuroadaptations may contribute to the complex manifestations of addiction but are poorly defined, especially in primates. The purpose of this application is to comprehensively investigate gene expression dysregulation within the reward circuit that may mediate compulsive cocaine taking, using nonhuman primate models of moderate or excessive cocaine self-administration. Monkeys self-administering cocaine will be yoked to monkeys passively receiving cocaine or saline injections for different exposure periods that reflect initial stages of addiction, or "recreational", drug use and more chronic cocaine use associated with addiction. A similar study will be conducted in which monkeys self-administer a non-drug reinforcer (sucrose pellets). We postulate that a dysregulation of the dopamine (DA) and glutamate (Glu) systems is associated with chronic cocaine taking. We further postulate that ensemble adaptations in multiple brain structures within the reward circuit as a consequence of DA/Glu dysregulation may accompany chronic cocaine taking. We specifically will investigate adaptations in mesocorticolimbic DA and Glu systems induced by initial and chronic cocaine self-administration by characterizing changes in key components of DA and Glu systems using in situ hybridization, quantitative PCR, and immunoblotting (Aim I). Aim II will define gene expression patterns at the genome level associated with initial and chronic cocaine self-administration, using a newly developed Rhesus Macaque Gene Chip. Successful completion of the proposed research will provide an integrated assessment of the DA and Glu systems, identify individual novel dysregulated gene candidates, and provide a near genome view of transcriptome changes associated with the reinforcing effects of cocaine in multiple brain structures within the reward circuit. The outcome of the research should deepen our understanding of the molecular and cellular basis of compulsive drug taking.